m6A methylation regulates hypoxia-induced pancreatic cancer glycolytic metabolism through ALKBH5-HDAC4-HIF1α positive feedback loop.

Pancreatic cancer (PC) is the most hypoxic cancer type among solid tumors. The dynamic changes of RNA N6-methyl-adenosine (m6A) contribute to tumor cells adaption to hypoxic microenvironmental. However, the regulatory mechanisms of hypoxia response in PC remains elusive. Here, we reported that the m6A demethylase ALKBH5 mediated a decrease of total mRNA m6A modification during hypoxia. Subsequently, methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined with RNA sequencing (RNA-seq) revealed transcriptome-wide gene expression alteration and identified histone deacetylase type 4 (HDAC4) as a key target gene of m6A modification under hypoxic conditionds. Mechanistically, m6A methylation recognized by m6A reader-YTHDF2 enhanced the stability of HDAC4, and then promoted glycolytic metabolism and migration of PC cells. Our assays also demonstrated that hypoxia-induced HDAC4 enhanced HIF1a protein stability, and overexpressed HIF1a promoted transcription of ALKBH5 in hypoxic pancreatic cancer cells. Together, these results found a ALKBH5/HDAC4/HIF1α positive feedback loop for cellular response to hypoxia in pancreatic cancer. Our studies uncover the crosstalk between histone acetylation and RNA methylation modification on layer of epigenetic regulation.